Survivin is a member of the Inhibitor of apoptosis (IAP) gene family containing a single Baculovirus IAP Repeat (BIR) domain, a zinc-finger fold, and an extended C-terminal helical coiled coil1. It is a homo-dimer of 16.5-kDa protein2,3. Ectopic survivin over-expression causes inhibition of cell death induced by intrinsic and extrinsic stimuli in cell lines4-9 and in animals10. Survivin is over-expressed essentially in all cancers, but not expressed in most adult normal tissues1,11. Survivin has also been shown to contribute to radiotherapy and chemotherapy resistance, and inhibition of survivin sensitizes cancer cells to these treatments12-14. Treatments with molecular probes such as antisense oligonucleotide, ribozyme, siRNA, and dominant negative mutant all resulted in caspase-dependent cell death and increased apoptosis induced by radiation and anticancer drugs14-19. These findings have established survivin as an ideal target for discovery of anticancer therapeutics.
Unfortunately, survivin belongs to a group of proteins that are considered “undruggable” due to lack of enzymatic activities. Although small molecule inhibitors have been identified that would interfere with the function of this type of proteins by blocking their interaction with other essential proteins, these approaches have generally not led to promising drug candidates.
In the case of survivin, targeting its expression has been attempted as an alternative to targeting survivin protein directly. For example, YM155, a small molecule compound, has been identified to inhibit survivin expression by targeting its transcription20. However, several phase II trials of YM155 showed only limited or modest at best efficacy on human cancers21. An antisense oligonucleotide, LY2181308, that inhibits survivin expression has also been tested as a single agent in phase I trial for solid tumors22 and in combination with docetaxel in phase II trial for castration-resistant prostate cancers23. Unfortunately, neither of these two trials showed any benefit of using LY2181308.
Thus, new inhibitors of survivin are clearly needed, perhaps based on a computational strategy to directly target the dimerization interface of survivin protein itself, a strategy that has not been attempted previously because survivin protein itself is considered “undruggable”.